There is a circadian variation in the frequency of ischemic episodes in patients with coronary artery disease. The heart rate threshold before the onset of ischemia in these episodes also varies during the day. To define the mechanisms responsible for these variations, we measured ischemic threshold during treadmill exercise tests and minimum forearm vascular resistance, as an index of minimum coronary vascular resistance, at different times of the day in patients with coronary artery disease. Ischemic threshold was defined as the heart rate at the onset of ST segment depression during exercise and minimum forearm vascular resistance was measured after 5 minutes of ischemia. In 15 patients studied, there was a strong inverse correlation between the minimum forearm vascular resistance and ischemic threshold, so that at the time of day when forearm vascular resistance was lowest, ischemic threshold was highest and vice versa. Furthermore, in the group as a whole, ischemic threshold was lower and vascular resistance higher in the morning and night compared to noon and evening. Thus, patients with coronary artery disease have a circadian variation in ischemic threshold which may be caused by an inverse circadian variation in coronary vascular resistance. These variations may account for the circadian variations in transient ischemic episodes and their variable threshold in patients with coronary artery disease. The mechanisms responsible for circadian variation in vascular resistance need to be further investigated.